the treatment of alcoholic hepatitis. - alcohol and alcoholism

Alcohol & Alcoholism, Vol. 31, No. 2, pp. 117-134. 1996

INVITED REVIEW

THE TREATMENT OF ALCOHOLIC HEPATITIS

MARSHA Y. MORGAN

Department of Medicine. The Royal Free Hospital. London NW3 2QG. UK

Abstract — Alcoholic hepatitis is a precirrhotic lesion; it develops in only a minority of chronic alcoholabusers even after decades of abuse The clinical spectrum of disease varies from asymptomatichepatomegaly to florid hepatocellular failure with gastrointestinal bleeding and hepatic encephalopathy.Corresponding variation is observed both in morbidity and mortality. The majority of individuals withmild to moderate alcoholic hepatitis improve significantly following abstinence from alcohol and theprovision of a diet sufficient to meet their nutritional requirements, their long-term outcome isdetermined largely by their ability to maintain abstinence from alcohol. Individuals with severe alcoholichepatitis require intensive nutritional support and vigorous management of the complications of theirliver injury; their outcome is generally poor. A small, carefully selected subgroup of these very sickpatients may benefit, at least in the short-term, from treatment with corticosteroids; the place oforthotopic hepatic transplantation. in this patient group, is still the subject of debate No other treatmentmodalities have been shown to confer benefit consistently. A number of new therapeutic approacheshave been proposed and need to be explored

INTRODUCTION

Alcoholic hepatitis develops in only a minority ofchronic alcohol abusers, even after decades ofabuse (Lelbach, 1966; Leevy, 1968). An unknownpercentage of individuals with this conditionremain asymptomatic and do not come to medicalattention; their liver injury may then heal inresponse to abstinence from alcohol, or else mayevolve silently to alcoholic cirrhosis, over time,particularly with continued drinking (Morgan,1991). Individuals with alcoholic hepatitis maycome to medical attention when incidentallyfound to have abnormal liver function tests orasymptomatic hepatomegaly. Alternatively, theymay present with complications such as jaundice,ascites, gastrointestinal bleeding and hepaticencephalopathy (Morgan, 1991). Symptomaticindividuals show variable morbidity and mortalityboth in the short- and long-term (Morgan, 1996).Progression to cirrhosis is observed more com-monly in women, in individuals who present withsevere disease and in those who continue to abusealcohol.

For individuals with mild to moderate alcoholichepatitis, the main therapeutic manoeuvres arethe removal of alcohol and the provision ofnutritional support. Further measures are

required in individuals who present with severealcoholic hepatitis in whom the short-term mor-tality rate may be as high as 60% (Morgan, 1996).A number of treatment options have been usedin this patient population, but with varyingdegrees of success (Morgan, 1991; Mezey, 1993;Morgan, 1993; Ramond et a/., 1993) (Table 1).

TREATMENT OPTIONS

Corticosteroids

Corticosteroids stimulate the appetite, increasehepatic albumin production and inhibit the pro-duction of Type I and Type IV collagen. In addi-tion, they possess both anti-inflammatory andimmunosuppressive properties. As such, they maybenefit patients with alcoholic hepatitis.

Table 1. Potential treatments for alcoholic hepatitis

CorticosteroidsHyperalimentationAnabolic steroidsInsulin/glucagonColchicinePropylthiouracilD-PenicillamineHepatoprotective agentsHepatic transplantation

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118 M. Y MORGAN

Between 1971 and 1992 the results of 13,randomized, controlled trials of the effects ofcorticosteroids, in patients with alcoholichepatitis, were published (Helman et al., 1971;Por te r s a/., 1971; Campra elal., 1973; Blitzer etal., 1977; Shumaker et al., 1978; Lesesne el al.,1978; Maddrey et al., 1978; Depew et al., 1980;Theodossi et al., 1982; Mendenhall et al., 1984;Bories et al. ,1987; Carithers et al. ,1989; Ramondet al., 1992). In addition, five separate meta-ana-lyses of data from selected studies were under-taken and individually reported (Reynolds et al.,1989; Imperiale and McCullough, 1990; Daures etal., 1991; Poynard et al., 1991; Christensen andGluud, 1995). Nevertheless, there is still no clearconsensus as to the benefits of this form of treat-ment.

In the studies conducted to date, the severity ofthe liver lesion varied considerably both withinand between study populations; this is reflectedin the short-term mortality rates in the controlpatients, which ranged from 10 to 100% (Table2). Histological confirmation of the diagnosis wasobtained from 30 to 100% of individuals in thevarious series; between 50 and 93% of the indi-

viduals biopsied had established cirrhosis.Inclusion and exclusion criteria varied betweenstudies; histological proof of diagnosis was aninclusion criterion in only three (Helman et al.,1971; Bories et al., 1987; Ramond et al., 1992);patients with gastrointestinal bleeding wereexcluded in most studies. Treatment regimensvaried both in terms of the drugs used, the dosageand reducing schedules and the time periodsemployed (Table 2). However, the usual treat-ment regimen was prednisolone 40 mg daily for4-6 weeks (Table 2). In all 13 studies the end-point was death, usually in relation to the trialperiod or the hospital inpatient stay, althoughsurvival rates at 3 months or beyond were reportedin some series.

In the first study, undertaken by Helman et al.(1971), 37 patients with alcoholic hepatitis, 27(76%) of whom had underlying cirrhosis, wererandomized to treatment with either prednisolone,40 mg daily, reducing over 6 weeks, or to a placebopreparation. Details were not provided of themortality rates at 1 month; however, the 3-monthmortality rate was significantly lower in the ster-oid-treated patients (5%) than in the control

Table 2. Controlled trials of corticosteroids in patients with alcoholic hepatitis of all grades of severity

First author

HelmanPorter

CampraBlitzerShumaker

LesesneMaddreyDepewTheodossiMendenhallBoriesCarithers

Ramond

Year

19711971

197319771978

1978197819801982198419871989

1992

Daily drug dosage

40 mg prednisolone reducing40 mg methylprednisolone i.v.

reducing oral0.5 mg/kgprednisone reducing40 mg prednisolone reducing30 mg methylprednisolone i.v.

reducing oral40 mg prednisolone reducing40 mg prednisolone reducing40 mg prednisolone reducing1 g methylprednisolone i.v.60 mg prednisolone reducing40 mg prednisolone32 mg methylprednisolone

oral/i.v. reducing40 mg prednisolone

Treatmentperiod

42103542264-7

21-2444

28-32423

303042

28

Control

Patientsn

179

251615

7311328882131

29

330

group

Deaths*n (%)

6(35)7(78)

9(36)2(13)7(47)

7 (100)4(13)7(54)

16 (57)18 (20)2(10)

11 (35)

16 (55)

112 (34)

Steroid

Patientsn

2011

201212

7241527902435

32

329

group

Deaths*/,(%)

1 (5)t6(55)

7(35)2(8)6(50)

2 (29)t1 (4)8(53)

17 (63)19(21)*1 (4)2(6)t

4 (13)t

76 (23)§

*At end of trial period except Helman (3-month mortality rates) and Theodossi (30-day mortality rates).tTrials in which treatment conferred significant benefit.+Values extrapolated from trial data and other publications.§Combined results suggest significant treatment effect.

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TREATMENT OF ALCOHOLIC HEPATITIS 119

Table 3. Effect of treatment with corticosteroids in patients with severe alcoholic hepatitis and spontaneous hepaticencephalopathy included in randomized, controlled, clinical trials

First author

HelmanPorterCampraBlitzerShumakerLesesneMaddreyDepewTheodossiMendenhallCarithersRamond

Year

197119711973197719781978197819801982198419891992

Control

Patientsn

68

10267

101314581910

163

group

Deaths*» (%)

6 (100)7(88)8(80)1 (50)4(67)7 (100)6 (60)7(54)

10(71)13 (22)9(47)6 (60)

84 (52)

Steroid

Patientsn

9783675

152061149

164

group

Deaths*/!(%)

l ( l l ) t6(86)4(50)2(66)2(33)2 (29)t1 (20)8(53)

19 (95)13 (21)*1 (7)t3 (33)t

62 (38)§

*At end of the trial period except Helman (3-month mortality rates) and Theodossi (30-day mortality rates).tTrials in which treatment conferred significant benefit.^Values extrapolated from trial data and other publications.§Combined results suggest significant treatment effect.

subjects (35%) (P < 0.01). Maximum benefit wasobserved in the most severely ill patients; thusthe mortality rate in patients with spontaneoushepatic encephalopathy, given steroids, was 11%compared with a mortality rate of 100% in theircounterparts given the placebo preparation (Table3).

This study has been criticized for a numberof reasons, but particularly because oral energyintakes in the patients who received the placebopreparation were substantially less than in thesteroid-treated individuals. A second trial was,therefore, undertaken by workers from the samedepartment, in which they ensured comparabledaily energy intakes in both the control and ster-oid-treated groups (Lesesne et al., 1978). In thistrial, the mortality rate at the end of the treatmentperiod was also significantly lower in the steroid-treated patients (29 vs 100%; P < 0.01) (Table 2).However, although the two patient groupsappeared balanced at randomization, the steroid-treated patients were probably less severely illand were certainly significantly younger than thepatients in the control group; both these factorswill have affected outcome.

Between 1971 and 1987 a further nine studiesof the effects of corticosteroids in patients with

alcoholic hepatitis were published, none of whichshowed benefit (Tables 2 and 3) (Porter et al.,1971; Campra et al., 1973; Blitzer et al., 1977;Shumaker et al., 1978; Maddrey et al., 1978;Depew et al., 1980; Theodossi et al., 1982;Mendenhall e/a/., 1984; Bones etal., 1987). Fourof these studies deserve separate mention.

Campra et al. (1973) randomized 45 patientswith alcoholic hepatitis to treatment with eitherprednisolone, 0.5 mg/kg daily, reducing over 6weeks, or to a placebo preparation. At the end ofthe treatment period, the mortality rates in thecontrol group (36%) and in the steroid-treatedgroup (35%) were comparable (Table 2). How-ever, patients with severe alcoholic hepatitiscomplicated by the development of spontaneoushepatic encephalopathy appeared to benefitselectively from treatment; thus, in this sub-population the mortality rates were 80% in thecontrol and 50% in the steroid-treated patients(Table 3). This observation prompted workersfrom the same department to undertake a secondstudy including only patients with severe alcoholichepatitis complicated by the presence of hepaticencephalopathy (Depew et al., 1980). However,treatment did not confer significant benefit; thewithin-trial mortality rate was approximately

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120 M. Y. MORGAN

50%, in both control and steroid-treated patients,with deaths occurring at similar rates and forsimilar reasons in both groups.

Maddrey et al. (1978) randomized 55 patientswith alcoholic hepatitis of varying severity to treat-ment with either prednisolone, 40 mg daily, or aplacebo preparation, for approximately 1 month.The 30-day mortality rates in the control (13%)and steroid-treated patients (4%) were com-parable (Table 2), as were the hospital inpatientmortality rates of 19% and 13%. Nevertheless, alldeaths occurred in the most severely ill patientsand discriminant function analysis showed thattreatment had a significant effect on survival.Further, these authors found that the formula:

Discriminant function = 4.6 (prothrombintime)(s) + serum bilirubin (mg/dl)

was useful in predicting survival; all deathsoccurred in patients in whom the discriminantfunction exceeded 93 on entry into the study.

The largest study, to date, was undertaken byMendenhall et al. (1984), who randomized 178patients with alcoholic hepatitis to treatment witheither prednisolone, 60 mg daily, reducing over30 days, or a placebo preparation. The 30-daymortality rates were comparable in both control(20%) and steroid-treated (21%) groups (Table2). Approximately two-thirds of the trial popu-lation had hepatic encephalopathy at the timeof enrollment and of these —20% died; again,however, steroids had no effect on the outcomein this subpopulation (Table 3).

In the last 6 years, two more carefully designedand executed studies have been published (Carith-ers et al., 1989; Ramond et al., 1992), both ofwhich reported a significant effect of treatmentwith corticosteroids on outcome. Carithers et al.(1989) randomized 66 patients with alcoholichepatitis, recruited from four centres, to treat-ment with either 32 mg of methylprednisolone,given orally or intravenously for 4 weeks, taperingover a further 2 weeks, or a placebo preparation.All patients had severe disease evidenced by thepresence of either spontaneous hepatic encephalo-pathy or a discriminant function of >32, cal-culated from the modified formula:Discriminant function =

4.6 (prothrombin time — control time)(s)serum bilirubin

The 28-day mortality rate in the steroid-treatedpatients (6%) was significantly lower than in thepatients receiving the placebo preparation (35%)(P < 0.006) (Table 2). In the subgroup of patientswith spontaneous hepatic encephalopathy, themortality rate in the steroid-treated patients (7%)was again significantly lower than in the controlgroup (47%) (P<0.02) (Table 3). This was awell-conducted study, but it has been criticizedbecause the diagnosis of alcoholic hepatitis wasnot confirmed histologically, nor were data pro-vided on outcome beyond the study period.

The most recent study, undertaken in twocentres by Ramond et al. (1992), employed thesame inclusion criteria and utilized a similartreatment regimen to that used by Carithers et al.(1989). In addition, however, the diagnosis ofalcoholic hepatitis was confirmed histologically inall patients and the follow-up period was pro-longed beyond 6 months. Sixty-one patients wererandomized to treatment with either prednisolone40 mg daily, or a placebo preparation, for 28 days.During the study, there were significantly fewerdeaths among the steroid-treated patients (13%)than among the patients receiving the placebopreparation (55%) (P < 0.001) (Table 2).Equally, the mean cumulative survival rates at 2months and 6 months were significantly higher inthe steroid-treated patients (88% and 84%) thanin the patients who had received the placeo pre-paration (45% and 45%) (Fig. 1). Subgroup ana-lysis showed that the use of steroids conferredsignificant benefit, independently of the presenceof hepatic encephalopathy (Fig. 2).

Between 1989 and 1995, five separate meta-analyses of available studies were undertaken todetermine whether treatment with corticosteroidsaffects short-term mortality in patients withalcoholic hepatitis (Reynolds et al., 1989; Imper-iale and McCullough, 1990; Daures et al., 1991;Poynard et al., 1991; Christensen and Gluud,1995). The results of these meta-analyses are con-flicting. Thus, Imperiale and McCullough (1990)concluded that, provided patients with gastro-intestinal bleeding were excluded, steroidsreduced the short-term mortality in patients withacute alcoholic hepatitis and hepatic encephalo-pathy. Poynard et al. (1991) concluded thatsteroids significantly reduced mortality in patientswith severe alcoholic hepatitis independently ofthe presence of hepatic encephalopathy, whereas

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c<uui_

0.

100

50 •

n

—«i Patient lost to follow-up

\

84 + 6%

45 + 9%

Placebo

90Days

180

Fig. 1. Survival in 61 patients with alcoholic hepatitis randomly assigned to receive either prednisolone 40 mg daily for28 days or a placebo preparation (Ramond et al., 1992)

100

0)Q.

••_ Corticosteroids without encephalopathy

"" Corticosteroids with encephalopthy

I Placebo without encephalopthy

Placebo with encephalopthy

35 70Days

Fig. 2. Survival in 61 patients with alcoholic hepatitis, randomly assigned to receive either prednisolone 40 mg daily for25 days or a placebo preparation: relationship to the presence or absence of hepatic encephalopathy (Ramond et al.,

1992)

Christensen and Gluud (1995) concluded thatsteroids have no significant effect on mortality inpatients with alcoholic hepatitis whether or notthey have hepatic encephalopathy.

The results of these meta-analyses must beviewed with caution, bearing in mind the resultsof the two best conducted studies to date (Car-ithers et al., 1989; Raymond et al., 1992). Thus,

overall, it would appear that corticosteroids do notaffect outcome in patients with mild to moderatealcoholic hepatitis, although they may signi-ficantly improve outcome in a small subgroup ofpatients with severe disease. These individualshave a discriminant function in excess of 32 andare free of gastrointestinal bleeding, bacterialinfection and significant renal failure.

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122 M. Y. MORGAN

Such individuals are, however, encounteredinfrequently; in the study by Carithers el al.(1989), only 66 patients fulfilling these criteriawere recruited from four centres in 5 years, whilein the study by Ramond et al. (1992), only 61 suchpatients were recruited from two centres in 3years. Once identified, these individuals shouldbe given 40 mg of prednisolone daily for 4 weeks,followed by 20 mg daily for 1 week and then10 mg daily for a final week. The complications oftreatment are surprisingly few, but patients shouldbe carefully monitored.

The treatment regimen may need to be modifiedin patients with evidence of past or present infec-tion with hepatitis B or C. Corticosteroids mayreactivate or increase viral replication and thismay have clinical consequences (Wands et al.,1975; Lok et al., 1991; Magrin et al., 1994);equally, withdrawal of corticosteroid treatmentmay be associated with the development of anacute hepatitis or even hepatic failure (Rakela etal., 1983; Thung etal., 1985). If these patients areto be treated at all, then the prednisolone dosageshould probably be reduced and its withdrawalprolonged beyond 2 weeks.

Nutritional supplementation

Very little information is available on thenutritional requirements of patients with alcoholichepatitis (Morgan, 1991; Miiller et al., 1994;Nompleggi and Bonkovsky, 1994). In a study byWeber and Reiser (1982), it was shown that thesepatients need protein intakes in the region of 70-100 g daily to ensure positive nitrogen balance. Itis also likely that their daily energy requirementsare increased, but this has not been documented,to date. Dietary intake may be limited by anorexiaand nausea with the result that a high percentageof total daily energy may be consumed as alcohol(Morgan, 1981). These patients are, in con-sequence, frequently malnourished and this has adetrimental effect on survival (Mendenhall et al.,1993). There is, therefore, a clear rationale forthe provision of nutritional supplementation inthis population.

A number of controlled studies have beenundertaken, which show that, in general, nutri-tional supplementation may improve nutritionalstatus and liver function in patients with alcoholichepatitis, but that it does not, in itself, improvesurvival (Nasrallah and Galambos. 1980; Calvey

et al., 1985; Diehl et al., 1985; Mendenhall et al.,1985; Naveau et al., 1986; Achord, 1987; Soberonet al., 1987; Simon and Galambos, 1988; Bon-kovsky et al., 1991a,b; Mezey etal., 1991; Kearnsetal., 1992).

A small number of studies have been under-taken in which nutritional supplements have beenprovided for patients with alcoholic hepatitis viaoral or enteral routes (Calvey et al., 1985; Men-denhall et al., 1985; Soberon et al., 1987; Kearns etal., 1992). Mendenhall et al. (1985), for example,assessed the effects of oral nutritional support onoutcome in 57 patients with moderate to severealcoholic hepatitis. Thirty-four patients weregiven a standard hospital diet and were allowedto eat ad libitum. The remaining 23 patients weregiven the same diet together with a dietary sup-plement high in calories, protein and branched-chain amino acids; both groups were monitoredover 30 days. At the end of the trial periodimprovements were observed in six of the ninevariables used to assess nutritional status in thepatients receiving the oral supplement, whereasthese variables were either unchanged or else haddeteriorated in the patients given the hospital dietalone; mortality rates were similar in the control(21%) and supplemented (17%) groups. Thesetwo dietary regimens were obviously not com-parable as they were neither isocaloric nor iso-nitrogenous. Thus, it is not possible to draw anyconclusions from this study on the benefits ofnutritional supplementation over provision of adiet adequate in calories and protein consumedad libitum.

Calvey et al. (1985) undertook a more detailedstudy in 64 patients with severe alcoholic hepatitis,all of whom were provided with a basic daily dietcontaining 1800-2400 kcal, 40-80 g of protein and22 mmol of sodium. Twenty-one patients receivedan additional 65 g of conventional protein and2000 non-protein calories daily, while a further 21patients received 45 g of conventional protein,25 g of branched-chain amino acids and 2000 non-protein calories daily. These supplements weregiven orally, enterally or, if necessary, intra-venously, for ~3 weeks.

No differences were observed in mortality ratesbetween the control (32%) and supplemented(38%) groups. Overall, the mortality rate wassignificantly higher in the patients who failed toachieve positive nitrogen balance independently

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of the dietary regimen used (58 vs 3%)(P < 0.001). This confirms the observation madeby Fiaccadori et al. (1984) that survival is sig-nificantly decreased in patients with chronic liverdisease who are unable to maintain nitrogen equi-librium.

Kearnsera/. (1992) randomized 31 patients withalcoholic hepatitis to receive, for 28 days, eithera standard hospital diet or the same diet supple-mented with a casein-based, enteral feed. Duringthe trial period, patients in the supplementedgroup showed a more rapid clearing of theirencephalopathy, a significant fall in their meanserum bilirubin concentration and a significantincrease in their mean antipyrine clearance. Themortality rates in the supplemented (13%) andnon-supplemented (27%) groups were, however,not significantly different. This study has beencriticized because the energy intake in the non-supplemented group met only 80% of predictedrequirements, whereas the intake in the sup-plemented group exceeded predicted require-ments by 70%. Likewise the daily protein intakesin the non-supplemented and supplementedgroups were widely disparate (50 vs 103 g). Thus,conclusions are difficult to draw. However, these

workers were able to show that it is possible tofeed these patients enterally and that enteral feedsare well-tolerated. Similar conclusions weredrawn by other workers (Soberon et al., 1987).

A total of seven controlled studies of the effectsof parenteral nutritional supplements in patientswith alcoholic hepatitis have been undertaken todate (Table 4) (Nasrallah and Galambos, 1980;Diehl et al., 1985; Naveau et al., 1986; Achord,1987; Simon and Galambos, 1988; Bonkovsky etal., 1991a,b; Mezey et al., 1991). Overall, thenumber of treated patients is small. The majorityof patients appear to have had mild to moderatealcoholic hepatitis as evidenced by the mortalityrates in the control populations which ranged fromzero to 22%. Histological confirmation of thediagnosis was obtained from zero to 100% ofpatients in the various studies; between zero and100% of the individuals biopsied had establishedcirrhosis. Inclusion and exclusion criteria variedbetween studies. All subjects were given a well-balanced, hospital diet which provided at least30 kcal/kg and 1 g of protein/kg daily and receivedoral supplements of multivitamins, folic acid andminerals. The experimental groups received, inaddition, a parenteral infusion of standard amino

Table 4. Effect of parenteral nutritional supplementation in patients with alcoholic hepatitis included in randomized,controlled, clinical trials

First author

NasrallahDiehl

Naveau

Achord

Simon

Bonkovsky

Mezey

Year

19801985

1986

1987

1988

1991

1991

Trial1 I Idl

duration(days)

2530

28

21

28

21

30

Control regimen(daily)

Standard dietStandard diet +

i.v. 130gglucose

Standard diet

Standard diet

Standard diet +132 g protein& 3200 kcalorally

Standard diet

Standard diet +i.v. 130gglucose

Experimental regimen(daily)

Standard diet + i.v.Standard diet + i v

130 g glucose

Standard diet + i.v.

70g a.a.*52g a.a. +

90 g a.a. +2800 kcal as glucose & lipid

Standard diet + i.v.200 g glucose

Standard diet + i.v.100 g glucose/50 j

Standard diet + i.v.lOOg glucose

Standard diet + i.v.130 g glucose

43g a.a. +

70 g a.a. +; lipid

70 g a a. +

52 g a a. +

Control

Patientsn

1810

20

14

18

12

26

group

Deathsn(%)

4(22)0 (0)

1 (5)

3(21)

3(17)

0 (0)

5(19)

Treatment group

Patientsn

175

20

14

16

9

28

; Deathsn

00

1

1

4

0

6

(%)

(0)t(0)

(5)

(7)

(25)

(0)

(21)

'a.a. = amino acids.tTrial in which the experimental regimen conferred benefit.

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124 M. Y. MORGAN

acids with or without glucose and lipid. In two ofthe studies the control group received an intra-venous infusion of glucose in addition to the stand-ard diet, while in a third study individuals in thecontrol group received an enteral supplement inaddition to their standard diet. Treatment wascontinued for between 21 and 30 days. A widerange of variables were used to assess both liverfunction and nutritional status and these variedconsiderably between studies. In all seven studies,however, the end-point was death.

The results of these studies are extremely dif-ficult to interpret because it is often unclear whatcomparisons workers were trying to make. Inseveral, the comparison made was ostensibly ofthe effects on outcome of a nutritionally adequatediet against a regimen providing excess proteinand calories. However, in the majority of thesestudies voluntary food intake was appreciably lessthan the amount offered and less than the amountrequired to sustain adequate nutritional status. Inconsequence, the comparisons made were effec-tively between regimens which were eithernutritionally adequate or nutritionally inad-equate.

Because of the difficulties inherent in inter-pretation of these data, conclusions cannot bedrawn. However, a number of observations canbe made; first, voluntary food intake is likelyto be poor in patients with moderate to severealcoholic hepatitis, with the result that they maynot be able to attain optimal nutrient intakeunaided; second, provision of adequate energyand protein intakes will result in improvementin nutritional status and liver function even inpatients who are severely ill, but has little effecton short-term mortality; third, no appreciableadverse events are associated with the provisionof high-calorie, high-protein nutritional sup-plements; these regimens are well-tolerated byeven the most severely ill patients without exacer-bation of fluid retention, azotaemia or hepaticencephalopathy.

Thus, it would seem essential to ensure that allpatients with alcoholic hepatitis are adequatelynourished. They should receive a minimum of30 kcal/kg and 1 g of protein/kg daily and thisshould be given, whenever possible, by the oralor enteral route; if difficulties are encountered inmeeting requirements, then a proportion shouldbe given parenterally, preferably via a peripheral

vein. Standard feeds and parenteral solutionsshould suffice. There is no evidence, at present,that provision of nutrients in excess of require-ments confers any additional benefit.

Anabolic steroids

Anabolic steroids might benefit patients withalcohol-related liver disease because of theireffects on nucleic acid and protein synthesis(Bengmark and Olsson, 1964). To date, threerandomized, controlled studies have been under-taken on the effects of anabolic steroids in patientswith alcoholic hepatitis (Mendenhall et al., 1984;Bonkovsky et al., 1991a,b; Mendenhall et al.,1993).

In the first study, Mendenhall et al. (1984)randomized 173 men with moderate to severealcoholic hepatitis to treatment with either ox-androlone, 80 mg daily, for 30 days, or a placebopreparation. The 30-day mortality rate was 13%in the moderately ill patients and 29% in theseverely ill patients; treatment with oxandrolonedid not affect the short-term outcome. In theindividuals with moderately severe alcoholichepatitis, who survived the first 30 days, a signifi-cant reduction was observed in the 6-month mor-tality rate in relation to treatment (3.5% vs 20%;P < 0.02). No such beneficial effect was observedin individuals with severe alcoholic hepatitis andoverall survival rates at 30 months were similar inthe oxandrolone and placebo-treated groups.

Bonkovsky et al. (1991a,b) randomized 39patients with moderate to severe alcoholic hepa-titis to 21 days' treatment with either oxandrolone80 mg daily, oxandrolone plus intravenous aminoacid supplementation, intravenous amino acidsupplementation alone, or to so-called 'standardtherapy'. No significant differences in outcomewere observed between the four groups, althoughimprovement in laboratory variables was mostmarked in individuals who received both ox-androlone and nutritional supplementation.

More recently, Mendenhall et al. (1993)randomized 273 men with moderate to severealcoholic hepatitis to treatment with either ox-androlone, 80 mg daily, for 30 days, and then40 mg daily for 60 days, or to a placebo prepara-tion. The oxandrolone-treated patients received,in addition, a branched-chain amino acid-enriched, oral supplement which provided 60 g ofprotein and 1600 kcal daily, for 30 days, and then

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Table 5. Mortality rates in patients with alcoholic hepatitis in relation to their degree of malnutrition, their daily calorieintake and treatment with oxandrolone (modified from Mendenhall el al.. 1993)

Oxandrolone

YesNo

Moderate

>2500 kcal/day

4%28%

malnutrition

<2500 kcal/day

30%33%

Severe

>25OO kcal/day

21%13%

malnutrition

<2500 kcal/day

59%45%

45 g of protein and 1200 kcal daily for the remain-ing 60 days.

Overall, the 6-month cumulative mortality ratewas 35% in patients receiving oxandrolone andnutritional supplementation and 39% in the con-trol subjects. No selective beneficial effect wasobserved in relation to disease severity as in theoriginal study carried out by this group(Mendenhall et al., 1984). However, a selectivebeneficial effect of treatment was observed inrelation to the degree of malnutrition. Thus, inpatients with moderate malnutrition, the 6-monthmortality rate was significantly lower in patientsreceiving the active treatment regimen than thecontrol regimen. No such effect was observed inthe patients with severe malnutrition.

In order to reconcile the results of their twotrials and to try to separate the beneficial effectsof nutritional supplementation from those ofoxandrolone, the above group, combined theirtwo study populations and re-analysed their data(Mendenhall et al., 1993). They showed thatpatients with alcoholic hepatitis who were mod-erately malnourished benefitted from treatmentwith oxandrolone, provided that their oral intake,whether supplemented or not, exceeded2500 kcal/day (Table 5). In these individuals, the6-month mortality rate was 4% compared to mor-tality rates of between 28% and 33% in theircounterparts whose dietary intake was inadequateor who were not receiving the anabolic steroid(Table 5). In patients with alcoholic hepatitis andsevere malnutrition, oxandrolone had no effecton outcome but mortality was significantly lowerin those individuals consuming in excess of2500 kcal/day (19% vs 51%; P< 0.001) (Table5).

These workers finally concluded that patientswith alcoholic hepatitis need vigorous nutritionalsupport, and if they are moderately malnourishedthey should also be given oxandrolone, althoughthey did not suggest a treatment regimen. Ox-

androlone is a relatively inexpensive drug and itsuse in the studies to date has been associatedwith few side-effects. It probably deserves furtherstudy.

Insulin and glucagon

A number of factors are known to control hep-atic regeneration in animals, of which the beststudied are insulin and glucagon (Baker, 1985). Itseems reasonable to assume that the mechanismscontrolling hepatic regeneration in humans aresimilarly regulated; the use of hepatotrophic fac-tors in the treatment of alcoholic hepatitis is basedon this assumption. To date, six randomized, con-trolled trials of insulin and glucagon in the treat-ment of alcoholic hepatitis have been undertaken(Baker et al., 1981; Mirouze et al., 1981; Radvanet al., 1982; Feher et al., 1987; Bird et al., 1991;Trinchet et al., 1992) (Table 6).

The results of the first trial, that by Baker et al.(1981), were encouraging, if inconclusive. Thus,although mean serum bilirubin concentrations andprothrombin times improved to a significantlygreater degree in the patients receiving insulinand glucagon, the 21-day mortality rates in thecontrol (24%) and treated patients (12%) werenot significantly different (Table 6).

Similarly encouraging but more conclusiveresults were reported by Feher et al. (1987). Intheir study, the mean serum bilirubin concen-tration, serum aspartate transaminase and y-glu-tamyl transpeptidase activities and prothrombintime improved significantly in the treatmentgroup, whilst only the mean serum bilirubin con-centration showed improvement in the controlgroup, and then to a lesser degree. In addition,the 21-day mortality rate in the treated patients(15%) was significantly less than in the controlsubjects (42%) {P < 0.02) (Table 6).

No significant benefits of treatment were, how-ever, reported in the remaining four studies(Mirouze etal., 1981; Radvan etal., 1982; Bird et

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Table 6.

Firstauthor

BakerMirouzeRadvanFeherBirdTrinchet

Effect of

Year

198119811982198719911992

treatment with

Trialduration(weeks)

322333

M. Y. MORGAN

insulin and glucagon in patients with alcoholic hepatitiscontrolled, clinical trials

Insulin(U/24h)

243648303030

Glucagon(mg/24h)

2.44.04.83.03.03.0

Control

Patientsn

251215334335

163

group

Deathsn (%)

6(24)7(58)7(47)

14 (42)14 (33)5(14)

53 (33)

included in randomized.

Treatment group

Patientsn

251416334337

168

Deathsn (%)

3(12)6(43)4(25)5(15) '

15 (35)10 (27)

43 (26)

"Trial in which treatment conferred significant benefit.

al., 1991; Trinchet et al., 1992) (Table 6).Hypoglycaemia was observed, as a complica-

tion, in all of these studies and resulted in thedeath of at least one treated patient (Baker et al.,1981). In addition, a number of difficulties arosein maintaining intravenous access for prolongedperiods of time. Given the potential complicationsand complexity of this form of treatment, and thelimited evidence of its efficacy, its use is not tobe recommended. A better understanding of themechanisms controlling hepatic regeneration, inman, might result in the development of moreuseful treatment regimens.

Colchicine

Colchicine inhibits granulocyte migration intoareas of inflammation and interferes with thedegradation of polymorphonuclear leucocytes(Malawista, 1975). It also inhibits microtubuleassembly (Olmstead and Borisy, 1973) and thetranscellular movement of collagen (Ehrlich andBornstein, 1972), and increases collagenaseactivity (Harris and Krane, 1971). Thus, on theor-etical grounds, it might attenuate the inflam-matory response associated with alcohol-relatedhepatocyte injury, and might diminish collagendeposition and enhance its dissolution.

Two randomized, controlled studies of col-chicine in the treatment of alcoholic hepatitis havebeen undertaken, neither of which reportedbenefit (Trinchet et al., 19896; Akriviadis et al.,1990). Thus, Akriviadis et al. (1990) treated 72'patients with severe alcoholic hepatitis with eithercolchicine, 1 mg daily, or a placebo preparation,for 30 days, and recorded death rates of 17%

in the control and 19% in the colchicine-treatedgroup. Similarly, Trinchet et al. (1989b) treated67 patients with histologically-proven alcoholichepatitis, 50% of whom had cirrhosis, with either1 mg of colchicine daily, or a placebo preparation,for 6 months; liver biopsies were repeated at 3and 6 months. Overall, no significant differenceswere observed in clinical, laboratory or his-tological variables between the two groups, overthe time-course of the study, although there wassome evidence of preferential histologicalimprovement in the colchicine-treated patients at3 months. Almost 60% of patients were lost tofollow-up during this trial, so that conclusions aredifficult to draw.

Thus, there is no evidence, at present, thatpatients with alcoholic hepatitis benefit from treat-ment with colchicine, at least in the short-term.

PropylthiouracilBoth alcohol and hypoxia produce liver injury

which is predominantly centrizonal in distri-bution. Oxygen consumption rates are increasedin animals with alcohol-induced liver injury and,if the liver oxygen supply is reduced, centrizonalnecrosis will develop (Israel et al., 1973, 1975a).These changes can be suppressed by thyroid-ectomy and abolished by use of propylthiouracil(Bernstein et al., 1975; Israel et al., 1975b). Ithas,therefore, been suggested that chronic alcoholabuse might produce a hypermetabolic statewithin the liver, in man, resulting in an increaseddemand for oxygen, and ultimately to centrizonalhypoxia. As such, treatment with propylthiouracilmight attenuate or even abolish these changes.

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To date, four randomized, controlled trials ofpropylthiouracil in the treatment of alcoholichepatitis have been undertaken (Orrego et al.,1979; Halle et al.. 1981; Serrano-Cancino et al.,1981; Peirrugues et al., 1989).

In the first study, Orrego et al. (1979) ran-domized 133 patients with alcohol-related liverdisease, 38 (29%) of whom had alcoholichepatitis, to treatment with either 300 mg of pro-pylthiouracil daily, or a placebo preparation, for6 weeks. The patients with alcoholic hepatitis whoreceived the active drug were said to show morerapid improvement in a number of clinical andlaboratory variables than those who received theplacebo preparation. However, few data wereprovided to support this assertion.

In the remaining three studies, treatment withpropylthiouracil was reported to be of little benefit(Halle et al., 1981; Serrano-Cancino et al., 1981;Peirrugues et al., 1989). Halle et al. (1981), forexample, randomized 67 patients with severealcoholic hepatitis to treatment with either 225 mgof propylthiouracil daily, or a placebo prepara-tion, for 6 weeks, and were unable to show anybeneficial effects of treatment on either morbidityor mortality. Approximately 20% of patients inboth control and treatment groups died, while13% of the treated patients became hypothyroid.

Thus, there is no evidence, at present, thatpatients with alcoholic hepatitis benefit from treat-ment with propylthiouracil. It should also beremembered that propylthiouracil itself caninduce fatal hepatic necrosis (Limaye andRuffolo, 1987).

D-Penicillamine

Penicillamine inhibits the cross-linkage of newlyformed collagen thus rendering it more sus-ceptible to the actions of collagenase (Nimni andBavetta, 1965). It might, therefore, reduce orimpede hepatic fibrogenesis and prevent pro-gression of alcoholic hepatitis. Resnick et al.(1974) randomized 40 patients with moderatelysevere alcoholic hepatitis to treatment with eitherD-penicillamine, 1 g daily, or a placebo pre-paration, for 8 weeks. Similar improvements wereobserved in mean serum bilirubin concentrationsand aspartate aminotransferase activities in bothgroups during the trial and the mortality rates of19% in the control and 16% in the penicillamine-treated patients were comparable. There were

reductions in the degree of hepatocellular necrosisand in the active deposition of collagen in liverbiopsies obtained from both groups of patients,but the improvements appeared greater in thepatients receiving the penicillamine. However,the number of paired pre- and post-treatmentbiopsies was too small for adequate statisticalanalysis of these histological changes in relationto treatment. Further short- and long-term studiesof penicillamine in the treatment of alcoholichepatitis are needed.

Hepatoprotective agents

A number of so-called 'hepatoprotectiveagents' are available and are used extensively,particularly in Continental Europe, for the treat-ment of alcoholic liver disease (Morgan, 1985)However, the evidence that their use confers anysignificant benefit is poor.

(+)-Cyanidanol-3 (Catechin) is the best knownand most extensively investigated hepato-protective agent (Morgan, 1985). It is a naturallyoccurring bioflavonoid which has antioxidant andmembrane-stabilizing properties and an ability toscavenge free radicals. It has been shown to nor-malize the NADH/NAD+ ratio, to increase ATPconcentrations, and to stabilize lysosomal mem-branes in the livers of rats with alcohol-relatedliver injury. Two short-term, double-blind, ran-domized, controlled trials of (+)-cyanidanol-3 inpatients with alcoholic hepatitis have been under-taken, to date (Henning, 1981; Sanchez-Tapias etal., 1981); no significant effects of treatment wereobserved after 2 weeks or 3 months of therapy.

Thioctic acid (a-lipoic acid) is a naturallyoccurring compound which is a cofactor in thepyruvate dehydrogenase and a--ketoglutaratedehydrogenase enzyme complexes forming partof the citric acid cycle; it also stimulates prosta-glandin synthesis via its action on prostaglandincyclooxygenase (Morgan, 1985). Apart from someevidence to suggest that it may be of value intreating liver failure following Amanita phalloidespoisoning, reports of its beneficial effects in liverdisease are largely anecdotal. Marshall et al.(1982) undertook a double-blind, randomized,controlled trial of thioctic acid, over 6 months, inpatients with pre-cirrhotic, alcohol-related liverdisease, including several with histologically pro-ven alcoholic hepatitis. No beneficial effects oftreatment were observed additional to those

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128 M. Y. MORGAN

reflecting abstinence from alcohol.Silymarin is the active principle of the fruit

Silybium marianum and consists of a complex ofthree isomeric compounds of the phenyl-chro-manone group (Morgan, 1985). Experimental andclinical studies suggest that it may have a favour-able effect on the course of various hepatic dis-orders. Trinchet et al. (1989a) undertook a short-term, double-blind, randomized, controlled trialof silymarin in patients with biopsy-provenalcoholic hepatitis. No significant benefits of treat-ment were observed additional to those reflectingabstinence from alcohol.

Thus, there is no evidence, at present, thatthese so-called 'hepatoprotective agents' benefitpatients with alcoholic hepatitis.

Hepatic transplantation

Orthotopic liver transplantation is associatedwith a 5-year survival of approximately 70%; ittherefore provides an excellent therapeutic optionfor many patients with end-stage chronic liverdisease (Neuberger, 1989; Starzl etal., 1989; Birdet al., 1990; Lucey, 1993). The suitability ofpatients with alcoholic liver disease as candidatesfor liver transplantation has been debated sincethe advent of hepatic transplantation programmesand clear guidelines are still lacking (Bird et al.,1990; Krom, 1994; Sherman and Williams, 1995).A number of objections have been raised to theconsideration of such patients as transplantrecipients; first, they may have other alcohol-related medical problems, such as cardiomyopa-thy, pancreatitis, neuropathy and malnutrition,which might impede their management andworsen their overall prognosis; second, they mayhave a variety of emotional, financial and socialproblems and may lack the support necessary towithstand the rigors of the transplant procedureand the months thereafter; many of these indi-viduals depend on social support which couldresult in financial burdens additional to the costsof the transplant procedure per se; third, theymight resume alcohol misuse/abuse followingtransplantation and this might lead to non-com-pliance with treatment regimens and damage tothe allograph; finally, inclusion of such patientsin transplant programmes might adversely affectdonor recruitment and might result in the defer-ment of treatment for patients with non-alcoholicliver disease.

Nevertheless, a number of centres now offer atransplant service to such patients. Little informa-tion is available from these centres on howmany patients with end-stage alcoholic liverdisease have been excluded from their transplantprogrammes because of the presence of otheralcohol-related disorders. Patients are rigorouslyevaluated before being accepted by transplantservices, and it is to be assumed that other organdamage is diligently sought, and, if identified andfound to be clinically significant, would be acontraindication, relative or definite, to can-didacy.

Where transplantation has been undertaken inpatients with alcoholic liver disease, outcomes aregood, both in terms of survival and quality of life,and do not differ substantially from those reportedin patients with non-alcoholic liver disease (Birdet al., 1990; Kumar et al., 1990; Knechtle et al.,1992; Lucey et al., 1993) (Fig. 3). Importantly, itincreases 2-year survival in the patients with themost severely decompensated disease (Poynard etal., 1994).

It was initially suggested that only individualswho had successfully abstained from alcohol for 6months or more should be considered as trans-plant candidates in order to lessen the risk ofrecidivism post-transplantation. Starzl et al.(1988), however, refuted this suggestion andshowed, in an early series, that 1-year recidivismrates were low even in individuals drinking up tothe time of transplantation. Campbell etal. (1993)warned, however, that early recidivism ratesshould be treated with caution, because in theirseries the early recidivism rate of 11.5% rose to32% by 3 years post-transplant. In many of thereported series recidivism rates were consistentlyhigher in individuals who were drinking up to thetime of transplantation compared with those whowere abstinent beforehand (Bird et al., 1990;Kumar et al., 1990). Indeed, Osorio et al. (1994)have shown that the single most important pre-dictor of abstinence post-transplantation isabstinence before the transplant procedure. How-ever, this view has recently been challenged byHoward et al. (1994), following their controlledassessment of 20 individuals who had been trans-planted for alcoholic liver disease some 1-6 yearspreviously. All had remained abstinent from al-cohol in the 7-10 months following surgery whenmedical supervision was at its closest, but there-

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100

80

>3U)<DO)TO

C

a>a>a.

60

40

20

12Months

24 36 48 60

Fig. 3 Actuarial patient survival after liver transplantation for alcoholic ( • ; n = 41) and non-alcoholic ( • ; n = 93) liverdisease in adult recipients (Knechtle ei al.. 1992)

after 80% had returned to drinking. Although themean alcohol intake was relatively modest at 25 gdaily, 40% were drinking above 'low-risk' levels,defined as 112 g/week for women and 168 g/weekfor men, 50% were binge-drinking intermittently,and 15% were drinking heavily and regularly.There was no relationship between alcohol con-sumption post-transplantation and the duration ofabstinence before the procedure.

The return to drinking post-transplantation isobviously not without consequence. Campbell etal. (1993) showed that 18% of their transplantrecipients were abusing alcohol sufficientlyseverely to require admission to hospital. Perhapsmore disturbing is the observation that severealcoholic liver injury develops rapidly in thegrafted liver in individuals who return to drinking(Baddour et al., 1992). Thus, in a group of 23 livergraft recipients who continued to abuse alcoholpost-transplantation, histological evidence ofalcoholic hepatitis was observed in all 23 within77-579 days of transplantation, whereas cirrhosiswas observed in four (Baddour et al., 1992). How-ard el al. (1994) reported on liver biopsies under-taken a mean of 36 months post-transplantationin eight patients, two of whom had returned toregular heavy drinking; cirrhosis was evident inthe biopsies from both of these patients.

The majority of patients with alcoholic liverdisease who are transplanted have end-stage

cirrhosis. There are very few reports of trans-plantation being undertaken for alcoholic hepa-titis per se. Bonet et al. (1993) have recently docu-mented their experience of transplanting cirrhoticindividuals with and without superadded alcoholichepatitis. The 1-year survival rates in the patientswith cirrhosis alone (81%) and in those with cir-rhosis and alcoholic hepatitis (89%) were com-parable. However, the 1-year post-transplantsobriety rate was 89% in the patients with cirrhosisalone, but only 51% in the patients with super-added alcoholic hepatitis. No details were givenof the patients' drinking behaviour pre-trans-plantation, but it is reasonable to assume that thepatients with alcoholic hepatitis were more likelyto have been actively abusing alcohol.

The results of this study have given rise to thesuggestions that the use of transplantation as atreatment option for patients with alcoholic hepa-titis has no place outside the setting of a well-designed controlled trial (Miller et al., 1994) orthat it should be abandoned altogether (Sorrell etal., 1994). Therefore, at present, no conclusionscan be drawn about the place of hepatic trans-plantation as a treatment for acute alcoholic hep-atitis.

POTENTIAL NEW THERAPEUTICAPPROACHES

A number of potential new therapeutic ap-

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130 M. Y. MORGAN

proaches to the treatment of alcoholic hepatitishave been identified (Mezey, 1993), some ofwhich are currently under investigation.

Lieber et al. (1994) have shown that oral sup-plementation with phosphatidylcholine preventsthe development of alcohol-related fibrosis andcirrhosis in non-human primates. They have ident-ified the active agent as dilinoleoylphosphat-idylcholine and have shown that it most likelyproduces its beneficial effects by promoting col-lagen breakdown. Clinical trials in patients withalcoholic liver disease are currently underway.Collagen degradation could also be enhanced byinsertion of exogenous DNA encoding amino orcarboxyterminal peptides of procollagen intohepatocytes (Wu etal., 1986). Alternatively, stepscould be taken to inhibit collagen synthesis, forexample, by use of proline analogues.

Cytokines, such as tumour necrosis factor, mayenhance hepatic necrosis and fibrosis and havebeen implicated in the genesis of alcoholic hep-atitis (McClain et al., 1993). The development ofantibodies to the relevant cytokines or to theirreceptors might provide a useful therapeuticapproach. Similarly, free oxygen radicals havebeen implicated in the genesis of alcohol-relatedliver injury (Nordman et al., 1992), so that stepseither to block their formation or to enhance theirmetabolism might prove therapeutically beneficial(Nordmann, 1994).

Finally, once the factors governing hepaticregeneration have been fully identified it might bepossible to stimulate the process and so enhancerecovery from alcohol-related liver injury.

the peripheral route.The outcome in patients with mild to moderate

alcoholic hepatitis is determined, to a large extent,by their ability to maintain abstinence fromalcohol. They should be carefully monitored overtime.

Patients with severe alcoholic hepatitis are lesseasily managed as the majority will already havecirrhosis. Many present with severe hepatocellularfailure with jaundice, ascites and hepaticencephalopathy and/or with the complications ofportal hypertension such as hypersplenism andbleeding oesophageal varices. Deterioration intheir clinical status and laboratory variables iscommonly seen following admission; the devel-opment of renal failure usually heralds a fataloutcome.

These patients should be managed in a specialistliver unit with the facilities to treat the com-plications of their liver disease; they shouldreceive intensive nutritional support. A small sub-group of carefully selected patients may benefit,at least in the short-term, from treatment withcorticosteroids. No firm recommendation can bemade about the value of other treatment modal-ities at present. The place of hepatic trans-plantation for these extremely sick patients is stillthe subject of debate.

The mortality rate in this population is high,exceeding 60% in some series. The outcome inthe survivors is, as in the patients with less severedisease, determined largely by their ability toremain abstinent from alcohol. They need carefullong-term monitoring.

A RATIONAL APPROACH TOTREATMENT

The majority of patients with mild to moderatealcoholic hepatitis will improve significantly fol-lowing abstinence from alcohol and the provisionof a diet sufficient to meet their nutritional needs.In general, therefore, they should ingest a mini-mum of 30 kcal and 1 g of protein per kg bodyweight daily. Dietary intake should be carefullymonitored and additional oral supplements pro-vided as indicated. If an adequate oral intakeis not achieved within 48 h, then nasogastric ornasojejunal feeding should be instituted. Ifnutritional requirements still cannot be met, thenparenteral feeding may be used, preferably using

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the treatment of alcoholic hepatitis. - alcohol and alcoholism

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